Process for the preparation of benzothiazolone compounds

ABSTRACT

There are described processes for the preparation of a compound of formula I                    
     and novel intermediates in the preparative process.

This application is a Divisional of Ser. No. 09/029,831, filed Mar. 10,1998 filed as PCT/SE98/00274, Feb. 17, 1998.

The present invention relates to a process for the preparation ofbenzothiazolone compounds and to novel intermediates in the process ofthe invention.

Benzothiazolone compounds are known. For example, WO 93/24473 describes7-(2-aminoethyl)-benzothiazolone compounds of general formula

wherein

X and Y independently represent —S(O)_(n)- or —O—,

n represents 0, 1 or 2,

p, q and r independently represent 2 or 3,

Z represents phenyl optionally substituted by halogen, —OR¹, NO₂ orNR²R³; or a 5- or

6-membered N, O, or S containing heterocycle, and

R¹, R² and R³ independent represent hydrogen or alkyl C₁₋₆,

and pharmaceutically acceptable derivatives thereof.

The compounds of WO 93/24473 may be prepared by any of several methods,for example by alkylation of the benzothiazolone compound of formula I

with an alkylating agent of formula

L-(CH₂)_(p)-X-(CH₂)_(q)-Y-(CH₂)_(r)-Z

in which p, q, r, X, Y and Z are as defined above and L represents aleaving group, or alkylation of a compound of formula I, as definedabove, with a compound of formula,

O═CH-(CH₂)_(p-1)-X-(CH₂)_(q)-Y-(CH₂)_(r)-Z

in which p, q, r, X, Y and Z are as defined above, in the presence of areducing agent.

The present invention relates in particular to a novel process for thesynthesis of compound I.

Routes for the synthesis of the compound are known, for example fromWeinstock et al, J Med. Chem., 1987, 30, 1166-1176.

According to the present invention, a process for the preparation of thecompound of formula I

comprises converting the chlorobenzothiazole compound of formula II

into the compound or formula I, for example using concentratedhydrobromic acid.

The compound of formula II is novel and may be prepared by halogenatingthe 2-aminobenzothiazole compound of formula III, for example usingcopper (II) chloride and copper (I) chloride and optionally ethanol, inHCl, e.g., 20% HCl to which is added sodium nitrite:

The compound of formula III is novel and may be prepared from a thioureaof formula IV,

using a halogenating/oxidising agent, for example N-bromosuccinimide,bromine or N-chlorosuccinimide in an acidic solvent, e.g., a mixed acidsolvent e.g. MeSO₃H/AcOH.

The compound of formula IV is novel and may be prepared by hydrolysis ofa compound of formula V

for example in water using a base such as K₂CO₃ or an alkali metalhydroxide, e.g. NaOH or KOH.

The compound of formula V is novel and may be prepared by reacting ananiline hydrochloride of formula VI

with benzoylisothiocyanate, for example in acetone ormethylisobutylketone (MIBK).

The compound of formula VI is novel and may be prepared by hydrogenatinga nitroacetamide of formula VII and treating with HCl

in any suitable solvent, for example in ethanol or 2-propanol, in thepresence of palladium on charcoal.

The compound of formula VII is novel and may be prepared by nitrating anacetamide of formula VIII

for example using HNO₃ in acetic acid.

The compound of formula VIII may be prepared from a compound of formulaIX:

for example using acetic anhydride or acetyl chloride, either as solventand reagent, or in the presence of dichloromethane and triethylamine.

In another aspect, the present invention provides a process for thepreparation of compounds of formula I comprising (i) converting acompound of formula IX into a compound of formula VIII, for exampleusing acetic anhydride or acetyl chloride, either as solvent andreagent, or in the presence of dichloromethane and triethylamine, and(ii) converting the compound of formula VIII into the compound offormula I, for example by the stepwise preparation of compounds VII, VI,V, IV, III and II as described above.

The process of the present invention provides an easy process for thepreparation of compound II, without the need to use undesirable startingmaterials, and giving the product compound in good yield.

The present invention also provides the novel compounds of formulae II,III, IV, V, VI and VII.

The following Example illustrates, but is not intended to limit, theinvention.

a) Under an atmosphere of nitrogen, 2-(4-methoxyphenyl)ethylamine (100g) was dissolved in dichloromethane. To this triethylamine (92.18 ml)was added and the resulting solution was cooled to 0° C. Aceticanhydride (62.40 ml) was added dropwise, over 35 mins, to the coldsolution. A maximum exotherm of 6° C. was observed. The reaction mixturewas stirred at room temperature for 40 mins. Tlc showed no trace ofstarting material on complete addition.

The reaction mixture was washed with dilute hydrochloric acid (2×1 L)and saturated NaHCO₃ solution (2×1 L) then dried over anhydrous MgSO₄,filtered and concentrated, in vacuo, to yield an off-white solid. Thiswas dried, in vacuo (T=40° C.).

b) A solution of 2-(4-methoxyphenyl)ethylacetamide (70 g) in glacialacetic acid (350 ml) was added, over 25 mins, to conc. nitric acid(339.6 ml) at 20° C. Cooling was applied so that the temperature wasmaintained between 18 and 20° C. The resulting solution was stirred atroom temperature (24° C.) for 45 mins. Reaction progress was monitoredby HPLC.

The reaction mixture was poured into iced water (2.7 L) forming aprecipitate/suspension. The product oiled out on stirring at roomtemperature. The mixture was extracted with dichloromethane (2×1 L). Asample of the extract was washed with NaHCO₃ dried and concentrated foranalysis. The extract was washed with saturated Na₂CO₃ solution (2×1 L),causing the extract to become saturated with water. The extract wasdiluted slightly with dichloromethane (˜100 ml), then dried overanhydrous MgSO₄, filtered and concentrated, in vacuo.

c) 2-(4-Methoxy-3-nitrophenyl)ethylacetamide (4.82 g) was dissolved inhot ethyl acetate (9.5 ml), then left to cool to room temperature.Cooling to 0° C. resulted in the formation of yellow crystals. Thesewere filtered off, washed with cold ethyl acetate, and dried in vacuo(T=40° C).

d) 2-(4-Methoxy-3-nitrophenyl)ethylacetamide (5.98 g) was dissolved inethanol (150 ml), 10% palladium on charcoal (0.18 g) was added and theresulting mixture was hydrogenated at 3 bar, overnight.

The catalyst was filtered off and the filtrate concentrated toapproximately one third of its volume. The solution was then gassed withhydrogen chloride until with cooling, a pale brown solid precipitatedout. The mixture was allowed to stir overnight. The off-white solid wasfiltered off washed with diethyl ether then dried, in vacuo, (T=50° C.).

e) The aniline hydrochloride (40.0 g) was dissolved in water (200 ml)and basified with aqueous sodium hydroxide solution (25% w/v) to pH≈11,extracted with dichloromethane (100 ml×3), dried (Na2SO₄) and evaporatedto dryness in vacuo to leave a pale pink solid. The solid was dissolvedin acetone (140 ml).

Ammonium thiocyanate (12.35 g) was dissolved in acetone (AR grade, 120ml) and benzoylchloride (17.3 ml) was added dropwise with stirring over2 mins. The temperature rose from 22° C. to 38° C. over the addition anda white precipitate formed. The reaction was stirred at room temperaturefor a further 75 mins and then filtered, and washed with acetone (20 ml)to give a solution of benzoylisothiocyanate. This was added dropwisewith stirring to the amine solution, over 40 mins. The temperature rosefrom 23° C. to 36° C. during the addition. A thick cream precipitateformed. The reaction was allowed to stir at room temperature for 16hours and then the product was collected by filtration, washed withwater (30 ml), sucked dry and then dried in vacuo at 60° C.

f) The N-benzoylthiourea (45.0 g) was suspended in water (330 ml).Sodium hydroxide solution (25% w/v, 58 ml) was added and the stirredmixture heated to 75-80° C. for 20 minutes.

The mixture was cooled to room temperature with the aid of a cold waterbath and then acidified to pH 7-8 using hydrochloric acid (˜4 N, 80 ml).

The mixture was cooled further in an ice bath—internal temp to 5° C.,stirred cold for 15 wins and the product collected by filtration, washedwith water (50 ml) and sucked dry. Dried in vacuo at 50° C.

g) Under an atmosphere of nitrogen, glacial acetic acid (112 ml) wasadded to methanesulfonic acid (823 ml). Cooling was required to keep thetemperature below 30° C. The thiourea (93.5 g) was added to theresulting solution at 28° C. The resulting solution was cooled to 2° C.for the addition over 30 mins, of a solution of N-bromosuccinimide(59.14 g) in methanesulfonic acid (187 ml). The temperature wasmaintained between 2 and 5° C. The resulting solution was stirred at ˜2°C. for 1 hour then allowed to stir at room temperature (max temp of ₃₀°C. observed) for 22 hours. Reaction progress was monitored by HTLC. Thereaction mixture was transferred to a dropping funnel then added, over3.5 hours to a 25% solution of sodium hydroxide (4.675 L) at 4° C. Thetemperature was maintained below 11° C. for the whole addition. Anoff-white solid precipitated from the reaction quench. The mixture wasstirred between 7-10° C. for 1.25 hours then filtered. The solid waswashed with water (2×200 ml), sucked dry, then dried in vacuo. (T=50°C.) to yield an off-white solid.

h) Under an atmosphere of nitrogen, 2-amino-benzothiazole (5 g) wasdissolved in concentrated hydrochloride acid at 22° C. To this was addedcopper (II) chloride (1.26 g), copper(I) chloride (0.93 g) and ethanol(0.32 g). Complete dissolution of the aminobenzothiazole was observed.The solution was cooled to 15° C. for the gradual addition, over 1.75hours, of an aqueous solution of sodium nitrite (3.9 g)—added below thesurface of the reaction mixture via a syringe pump. The temperature wasmaintained between 13 and 18° C. N₂ evolution was observed. The reactionprogress was monitored by HPLC. After 1.75 hours stirring at roomtemperature, the reaction mixture was quenched, over 5 mins, intostirred water at room temperature. A milky yellow solution was formed inwhich the product oiled out towards the end of the addition. The mixturewas stirred for 60 hours. The solid was filtered off, washed with water(250 ml), air dried then dried, in vacuo (T=55 C.), yielding on orangesolid.

i) The chlorobenzothiazole (15.0 g) was suspended in concentratedhydrobromic acid (165 ml) under a nitrogen atmosphere and the mixtureheated under reflux for 7.5 hours. The mixture was allowed to coolovernight and the precipitated product was collected by filtration,washed with isopropanol (20 ml) and sucked dry to give a yellow-brownpowder which was dried in vacuo at 45° C.

j) The hydrobromide salt (13.3 g) was suspended in water (130 ml) andwarmed to 80-90° C. under a nitrogen atmosphere. Further water (20 ml)was added. Charcoal (1.1 g) was added and the solution/suspensionstirred at ˜70° C. for 15 minutes and then filtered hot to give a clearsolution.

Concentrated hydrochloric acid (18 ml) was added to the filtrate and themixture left to stir under nitrogen overnight. The solid was collectedby filtration, washed with isopropanol (20 ml) and sucked dry to give ayellow powder, which was dried in vacuo at 45° C.

The product (5.0 g) was suspended in water (50 ml) under a nitrogenatmosphere and warmed to ˜70° C. Charcoal (0.3 g) was added and themixture stirred for 10 minutes and then filtered slowly to give a paleyellow solution. Concentrated hydrochloric acid (7 ml) was added and themixture stirred and allowed to cool under nitrogen. The precipitatedproduct was collected by filtration, washed with isopropanol (10 ml),sucked dry to give a pale yellow powder, and dried in vacuo at 45° C.

What is claimed is:
 1. A compound of formula X

wherein Y is H and X is selected from the group consisting of NO₂,NH₂-HCl, NH—CS—NHCOPh and NH—CS—NH₂, or X and Y together form afive-membered ring, as in formula II

or as in formula III


2. A compound of formula V: